Two polymorphs of afobazole from powder diffraction data

Afobazole {systematic name: 2-[2-(morpholin-4-yl)ethyl­sulfan­yl]-1H-benzimidazole} is a new anxiolytic drug and Actins, Auzins & Petkune [(2012). Eur. Patent EP10163962] described four polymorphic modifications. In the present study, the crystal structures of two monoclinic polymorphs, 5-eth­oxy-2-[2-(morpholin-4-ium-4-yl)ethyl­sulfan­yl]-1H-benz­imidazol-3-ium dichloride, C₁₅H₂₃N₃O₂S²⁺·2Cl^-, (II) and (IV), have been established from laboratory powder diffraction data. The crystal packing and conformation of the dications in (II) and (IV) are different. In (II), there are channels in the [001] direction, which offer atmospheric water mol­ecules an easy way of penetrating into the crystal structure, thus explaining the higher hygroscopicity of (II) compared with (IV).

S1. Comment

Afobazole {systematic name: 5-ethoxy-2-[2-(morpholin-4-ium-4-yl)ethylsulfanyl]-1H-benzimidazol-3-ium dichloride} is a new drug belonging to the class of 2-mercaptobenzimidazole derivatives. Afobazole exhibits pronounced anxiolytic action that is not accompanied by the side effects typical of tranquilizers of the benzodiazepine series. It does not produce sedative (calming), hypnotic and myorelaxant effects, and is still under intensive study (Cuevas et al., 2011a,b; Reutova et al., 2010). Clinical trials have shown afobazole to be well tolerated and reasonably effective for the treatment of anxiety, although its mechanism of action remains poorly defined. The physicochemical properties of afobazole have been studied and methods for its standardization developed (Milkina et al., 2006), but no published crystal structures were found in the Cambride Structural Database (CSD, Version 5.33; Allen, 2002). Recently, four polymorphic modifications of afobazole [(I), (II), (III) and (IV)] were reported by Actins et al. (2012). Herein, we report the crystal structures of the polymorphic salts (II) and (IV) determined from laboratory powder diffraction data.

The asymmetric units of (II) and (IV) are shown in Fig. 1. In both polymorphs, the geometry of the cation is normal and the morpholine ring has a chair conformation. However, the overall conformations of the cation in (II) and (IV) are different, as can be seen from Figs. 1 and 2. The crystal packings of (II) and (IV) are also different. In (II), classical intermolecular N—H···Cl hydrogen bonds (Table 1) link two cations and four anions into an electroneutral centrosymmetric unit (Fig. 3, top) and weak C—H···O interactions (Table 1) consolidate the crystal packing further. In (IV), intermolecular N—H···Cl hydrogen bonds (Table 2) link cations related by translation along the a axis and anions into electroneutral chains (Fig. 3, bottom), which are further held together by weak C—H···O interactions (Table 2).

Thermogravimetric analysis (TGA) shows that (IV) is stable at a relative humidity of 55 (3)% and T = 295 K over a period of 8 h, while (II) is hygroscopic, exhibiting a weight increase of 2.4% after 2 h exposure under the same conditions. However, the water content in the studied sample of (II), estimated by Karl Fischer titration, suggested no more than one water molecule per ten formula units of afobazole. These ambiguous data, along with the observed difference of 18 ų in the asymmetric unit-cell volumes of (II) and (IV), necessitated a check for the possible presence of solvent water in (II). In the crystal structure of (II), PLATON (Spek, 2009) detects solvent-accessible voids of 12 ų centred at (0.08, 0.81, 0.99). Atom OW was placed in the centre of the void, with an initial occupancy of 0.5 and a U_iso value fixed at 0.1 Å^-2, and refined. The atomic coordinates and occupancy factor of atom OW refined to (0.08, 0.80, 1.09) and 0.1 (2), respectively, with insignificant improvements in the R factors, which allows us to consider the investigated sample of form (II) as anhydrous. On the other hand, atom OW in the refined position has a reasonable environment and forms hydrogen bonds with atoms O19 (OW···O19 = 2.73 Å) and Cl1 [OW···Cl1(x, -y + 3/2, z + 1/2) = 3.10 Å], thus showing the position where an atmospheric water molecule could be docked without rearrangement of the crystal structure. Interestingly, the voids found by PLATON in (II) form sinuous channels in the [001] direction (Fig. 4), which offer water molecules an easy way of penetrating into the crystal structure.

In conclusion, we can state that crystal-packing features are responsible for the high hygroscopicity of (II) and therefore afobazole form (IV) is superior for prolonged storage.

Related literature

For related literature, see: Actins et al. (2012); Allen (2002); Cuevas et al. (2011a, 2011b); Dollase (1986); Laikov (1997, 2004, 2005); Laikov & Ustynyuk (2005); Milkina et al. (2006); Pawley (1981); Perdew et al. (1996); Popa (1998); Reutova et al. (2010); Spek (2009); Toraya (1986); Visser (1969); Werner et al. (1985); Zhukov et al. (2001); Zlokazov (1992, 1995); Zlokazov & Chernyshev (1992).

S2. Experimental

Samples of (II) and (IV) were prepared in polycrystalline form by JSC Grindeks (Riga, Latvia) according to the procedure of Actins et al. (2012). Thermogravimetric analysis was performed on 8–10 mg samples with an EXSTAR6000 TG/DTA 6300 analyser (Seiko, Japan) using open sample pans (5 mm; P/N SS000E030) in an air atmosphere at a heating rate of 10 K min^-1 over the temperature range 303–393 K.

S3. Refinement

The X-ray powder diffraction data were collected using a Huber G670 Guinier camera (Cu K_α1 radiation, λ = 1.54059 Å) equipped with an imaging-plate detector. The monoclinic unit-cell dimensions for both polymorphs were determined using three indexing programs: TREOR90 (Werner et al., 1985), ITO (Visser, 1969) and AUTOX (Zlokazov, 1992, 1995). Based on systematic extinctions, the space group for both (II) and (IV) was determined to be P2₁/c. The unit-cell parameters and space groups were further tested using a Pawley fit (Pawley, 1981) and confirmed by crystal structure solution. The powder pattern of (IV) contains four very weak peaks (d spacings = 15.629, 15.278, 14.453 and 5.694 Å) from other polymorphic forms of afobazole.

The crystal structures were solved using the simulated annealing technique (Zhukov et al., 2001). The Cambridge Structural Database (Version 5.33; Allen, 2002) contains no structures with the 5-ethoxy-2-(2-morpholinoethylthio)benzimidazole fragment. Therefore, the initial molecular model was obtained in the course of density functional theory (DFT) calculations in vacuo using the quantum-chemical program PRIRODA (Laikov, 1997, 2004, 2005; Laikov & Ustynyuk, 2005), employing the generalized-gradient approximation (GGA) and the PBE exchange-correlation function (Perdew et al., 1996). In simulated annealing runs (without H atoms), the total number of varied degrees of freedom (DOF) for (II) and (IV) was 18, i.e. nine translational (for two anions and one cation), three orientational and six torsional for the cation. The solutions found were fitted using the program MRIA (Zlokazov & Chernyshev, 1992) in bond-restrained Rietveld refinements using a split-type pseudo-Voigt peak-profile function (Toraya, 1986). In the refinement of (IV), the anisotropic line broadening was taken into account with the use of nine variables (Popa, 1998) and the March–Dollase (Dollase, 1986) formalism was used for correction of the preferred orientation in the [001] direction. Restraints were applied to the intramolecular bond lengths and contacts (<2.8 Å); the strength of the restraints was a function of interatomic separation and, for intramolecular bond lengths, corresponded to an r.m.s. deviation 0.02 Å. Additional restraints were applied to the planarity of the benzimidazole fragment with the attached atoms, with the maximum allowed deviation from the mean plane being 0.03 Å. All non-H atoms were refined isotropically. H atoms were positioned geometrically (C—H = 0.93–0.97 Å and N—H = 0.86–0.91 Å) and not refined. The diffraction profiles for both polymorphs after the final bond-restrained Rietveld refinements are shown in Fig. 5.

Computing details

For both compounds, data collection: G670 Imaging-Plate Guinier Camera Software (Huber, 2002); cell refinement: MRIA (Zlokazov & Chernyshev, 1992); data reduction: G670 Imaging-Plate Guinier Camera Software (Huber, 2002); program(s) used to solve structure: simulated annealing (Zhukov et al., 2001); program(s) used to refine structure: MRIA (Zlokazov & Chernyshev, 1992); molecular graphics: PLATON (Spek, 2009) and Mercury (Macrae et al., 2008); software used to prepare material for publication: MRIA (Zlokazov & Chernyshev, 1992) and SHELXL97 (Sheldrick, 2008).

Figures

	Fig. 1. The asymmetric units of (II) (top) and (IV) (bottom), showing the atomic numbering; the numbering of the C atoms in (IV) corresponds to that in (II). Displacement ellipsoids are drawn at the 50% probability level. Dashed lines denote hydrogen bonds.
	Fig. 2. A schematic representation of the cation conformation in (II) (lighter line; blue in electronic version of the paper) and (IV) (darker line; red), viewed along the C8—C9 bond. H atoms have been omitted for clarity.
	Fig. 3. Portions of the crystal packing in (II) (top) and (IV) (bottom). Dashed lines denote hydrogen bonds. C-bound H atoms have been omitted for clarity. [Symmetry codes: (i) -x + 1, -y + 1, -z + 1; (ii) x + 1, y, z.]
	Fig. 4. A space-filling representation of the crystal packing of (II), viewed along the c axis and showing the channels in the [001] direction.
	Fig. 5. The final Rietveld plots for (II) (top) and (IV) (bottom). The experimental diffraction profiles are indicated by dots (black). The calculated diffraction profiles are shown as the upper solid lines (red in the electronic version of the paper), the difference profiles are shown as the lower solid lines (blue) and the vertical bars (green) between the solid lines correspond to the positions of the Bragg peaks.

(II) 5-Ethoxy-2-[2-(morpholin-4-ium-4-yl)ethylsulfanyl]-1H-benzimidazol-3-ium dichloride

Crystal data

C15H23N3O2S^2+·2Cl^−	F(000) = 800
Mr = 380.33	Dx = 1.322 Mg m^−3
Monoclinic, P21/c	Melting point: 473 K
Hall symbol: -P 2ybc	Cu Kα1 radiation, λ = 1.54059 Å
a = 14.4952 (15) Å	µ = 4.17 mm^−1
b = 16.5419 (19) Å	T = 298 K
c = 7.9715 (8) Å	Particle morphology: no specific habit
β = 90.858 (15)°	white
V = 1911.2 (4) Å^3	flat sheet, 15 × 1 mm
Z = 4	Specimen preparation: Prepared at 298 K and 101 kPa

Data collection

Huber G670 Guinier camera diffractometer	Data collection mode: transmission
Radiation source: line-focus sealed tube	Scan method: continuous
Curved germanium(111) monochromator	2θmin = 4.00°, 2θmax = 76.00°, 2θstep = 0.01°
Specimen mounting: thin layer in the specimen holder of the camera

Refinement

Refinement on Inet	Profile function: split-type pseudo-Voigt (Toraya, 1986)
Least-squares matrix: full with fixed elements per cycle	127 parameters
Rp = 0.019	68 restraints
Rwp = 0.022	0 constraints
Rexp = 0.013	H-atom parameters not refined
RBragg = 0.059	Weighting scheme based on measured s.u.'s
χ^2 = 2.870	(Δ/σ)max = 0.003
7201 data points	Background function: Chebyshev polynomial up to the 5th order
Excluded region(s): none	Preferred orientation correction: none

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
N1	0.7461 (7)	0.6121 (7)	0.4652 (14)	0.063 (5)*
H1	0.7658	0.5638	0.4481	0.076*
C2	0.6643 (10)	0.6304 (8)	0.5351 (17)	0.061 (7)*
N3	0.6580 (8)	0.7131 (7)	0.5384 (14)	0.059 (5)*
H3	0.6126	0.7400	0.5788	0.071*
C4	0.7628 (10)	0.8279 (10)	0.4499 (18)	0.070 (7)*
H4	0.7268	0.8704	0.4880	0.084*
C5	0.8488 (11)	0.8408 (8)	0.370 (2)	0.067 (6)*
C6	0.9048 (11)	0.7742 (9)	0.3214 (19)	0.067 (7)*
H6	0.9597	0.7846	0.2667	0.080*
C7	0.8805 (11)	0.6946 (9)	0.3518 (19)	0.070 (6)*
H7	0.9193	0.6519	0.3254	0.084*
C8	0.7940 (10)	0.6819 (9)	0.4248 (16)	0.057 (6)*
C9	0.7361 (10)	0.7474 (10)	0.467 (2)	0.074 (6)*
O10	0.8822 (6)	0.9136 (5)	0.3406 (11)	0.054 (4)*
C11	0.9669 (10)	0.9267 (9)	0.2491 (18)	0.061 (6)*
H11A	0.9644	0.8987	0.1421	0.073*
H11B	1.0196	0.9069	0.3132	0.073*
C12	0.9743 (11)	1.0180 (9)	0.2224 (17)	0.069 (7)*
H12A	1.0295	1.0299	0.1619	0.104*
H12B	0.9766	1.0447	0.3292	0.104*
H12C	0.9216	1.0367	0.1592	0.104*
S13	0.5883 (3)	0.5626 (2)	0.6276 (5)	0.053 (2)*
C14	0.4898 (11)	0.6262 (9)	0.6950 (18)	0.066 (6)*
H14A	0.5112	0.6774	0.7406	0.079*
H14B	0.4475	0.6366	0.6022	0.079*
C15	0.4433 (10)	0.5741 (9)	0.8325 (18)	0.069 (7)*
H15A	0.4379	0.5187	0.7941	0.083*
H15B	0.4813	0.5745	0.9337	0.083*
N16	0.3487 (8)	0.6070 (7)	0.8707 (14)	0.059 (5)*
H16	0.3102	0.5922	0.7849	0.071*
C17	0.3482 (11)	0.6998 (9)	0.879 (2)	0.075 (6)*
H17A	0.3932	0.7181	0.9624	0.090*
H17B	0.3649	0.7221	0.7715	0.090*
C18	0.2532 (10)	0.7292 (9)	0.9263 (19)	0.071 (7)*
H18A	0.2547	0.7875	0.9389	0.086*
H18B	0.2101	0.7165	0.8358	0.086*
O19	0.2213 (6)	0.6943 (6)	1.0765 (10)	0.058 (4)*
C20	0.2146 (10)	0.6087 (10)	1.0605 (17)	0.069 (6)*
H20A	0.1734	0.5953	0.9675	0.083*
H20B	0.1891	0.5861	1.1620	0.083*
C21	0.3101 (10)	0.5720 (8)	1.0300 (18)	0.066 (7)*
H21A	0.3511	0.5841	1.1240	0.079*
H21B	0.3051	0.5137	1.0199	0.079*
Cl1	0.2325 (3)	0.5693 (2)	0.5691 (5)	0.0539 (18)*
Cl2	0.5306 (3)	0.8426 (2)	0.6990 (5)	0.0601 (19)*

Geometric parameters (Å, º)

N1—C2	1.352 (18)	C12—H12C	0.96
N1—C8	1.388 (19)	S13—C14	1.859 (16)
N1—H1	0.86	C14—C15	1.56 (2)
C2—N3	1.372 (18)	C14—H14A	0.97
C2—S13	1.743 (14)	C14—H14B	0.97
N3—C9	1.396 (19)	C15—N16	1.510 (19)
N3—H3	0.86	C15—H15A	0.97
C4—C9	1.39 (2)	C15—H15B	0.97
C4—C5	1.42 (2)	N16—C21	1.510 (18)
C4—H4	0.93	N16—C17	1.537 (18)
C5—O10	1.321 (17)	N16—H16	0.91
C5—C6	1.43 (2)	C17—C18	1.51 (2)
C6—C7	1.38 (2)	C17—H17A	0.97
C6—H6	0.93	C17—H17B	0.97
C7—C8	1.41 (2)	C18—O19	1.414 (17)
C7—H7	0.93	C18—H18A	0.97
C8—C9	1.41 (2)	C18—H18B	0.97
O10—C11	1.438 (17)	O19—C20	1.424 (19)
C11—C12	1.53 (2)	C20—C21	1.53 (2)
C11—H11A	0.97	C20—H20A	0.97
C11—H11B	0.97	C20—H20B	0.97
C12—H12A	0.96	C21—H21A	0.97
C12—H12B	0.96	C21—H21B	0.97
C2—N1—C8	110.8 (12)	C15—C14—H14A	111.1
C2—N1—H1	124.6	S13—C14—H14A	111.1
C8—N1—H1	124.6	C15—C14—H14B	111.0
N1—C2—N3	106.9 (12)	S13—C14—H14B	111.0
N1—C2—S13	126.5 (11)	H14A—C14—H14B	109.0
N3—C2—S13	126.2 (11)	N16—C15—C14	110.3 (12)
C2—N3—C9	110.0 (12)	N16—C15—H15A	109.6
C2—N3—H3	124.9	C14—C15—H15A	109.6
C9—N3—H3	125.0	N16—C15—H15B	109.6
C9—C4—C5	115.7 (14)	C14—C15—H15B	109.6
C9—C4—H4	122.1	H15A—C15—H15B	108.1
C5—C4—H4	122.2	C21—N16—C15	112.4 (11)
O10—C5—C4	122.9 (13)	C21—N16—C17	110.1 (11)
O10—C5—C6	116.3 (13)	C15—N16—C17	111.9 (11)
C4—C5—C6	120.8 (13)	C21—N16—H16	107.4
C7—C6—C5	122.6 (14)	C15—N16—H16	107.4
C7—C6—H6	118.7	C17—N16—H16	107.4
C5—C6—H6	118.7	C18—C17—N16	109.7 (12)
C6—C7—C8	116.5 (14)	C18—C17—H17A	109.7
C6—C7—H7	121.8	N16—C17—H17A	109.7
C8—C7—H7	121.7	C18—C17—H17B	109.8
N1—C8—C7	132.3 (13)	N16—C17—H17B	109.7
N1—C8—C9	106.4 (12)	H17A—C17—H17B	108.3
C7—C8—C9	121.3 (14)	O19—C18—C17	112.9 (12)
C4—C9—N3	131.0 (14)	O19—C18—H18A	109.0
C4—C9—C8	122.8 (14)	C17—C18—H18A	109.0
N3—C9—C8	105.9 (13)	O19—C18—H18B	109.1
C5—O10—C11	122.7 (11)	C17—C18—H18B	109.1
O10—C11—C12	106.2 (11)	H18A—C18—H18B	107.7
O10—C11—H11A	110.4	C18—O19—C20	110.7 (10)
C12—C11—H11A	110.5	O19—C20—C21	110.3 (12)
O10—C11—H11B	110.4	O19—C20—H20A	109.6
C12—C11—H11B	110.5	C21—C20—H20A	109.6
H11A—C11—H11B	108.7	O19—C20—H20B	109.6
C11—C12—H12A	109.5	C21—C20—H20B	109.6
C11—C12—H12B	109.5	H20A—C20—H20B	108.1
H12A—C12—H12B	109.5	N16—C21—C20	109.1 (11)
C11—C12—H12C	109.5	N16—C21—H21A	109.8
H12A—C12—H12C	109.4	C20—C21—H21A	109.9
H12B—C12—H12C	109.4	N16—C21—H21B	109.8
C2—S13—C14	104.5 (7)	C20—C21—H21B	109.9
C15—C14—S13	103.5 (10)	H21A—C21—H21B	108.3

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···Cl1^i	0.86	2.21	3.030 (12)	160
N3—H3···Cl2	0.86	2.29	3.116 (12)	161
N16—H16···Cl1	0.91	2.08	2.981 (12)	172
C15—H15B···Cl2^ii	0.97	2.61	3.453 (15)	145
C18—H18A···Cl1^ii	0.97	2.61	3.536 (15)	160
C18—H18B···O19^iii	0.97	2.55	3.091 (17)	115

Symmetry codes: (i) −x+1, −y+1, −z+1; (ii) x, −y+3/2, z+1/2; (iii) x, −y+3/2, z−1/2.

(IV) 5-Ethoxy-2-[2-(morpholin-4-ium-4-yl)ethylsulfanyl]-1H-benzimidazol-3-ium dichloride

Crystal data

C15H23N3O2S^2+·2Cl^−	F(000) = 800
Mr = 380.33	Dx = 1.373 Mg m^−3
Monoclinic, P21/c	Melting point: 482 K
Hall symbol: -P 2ybc	Cu Kα1 radiation, λ = 1.54059 Å
a = 9.7910 (11) Å	µ = 4.33 mm^−1
b = 18.2689 (19) Å	T = 298 K
c = 10.5687 (12) Å	Particle morphology: prism
β = 103.225 (17)°	white
V = 1840.3 (4) Å^3	flat sheet, 15 × 1 mm
Z = 4	Specimen preparation: Prepared at 298 K and 101 kPa

Data collection

Huber G670 Guinier camera diffractometer	Data collection mode: transmission
Radiation source: line-focus sealed tube	Scan method: continuous
Curved germanium(111) monochromator	2θmin = 4.00°, 2θmax = 76.00°, 2θstep = 0.01°
Specimen mounting: thin layer in the specimen holder of the camera

Refinement

Refinement on Inet	Profile function: split-type pseudo-Voigt (Toraya, 1986); anisotropic line-broadening has been taken into account with nine varied parameters (Popa, 1998)
Least-squares matrix: full with fixed elements per cycle	137 parameters
Rp = 0.023	68 restraints
Rwp = 0.030	0 constraints
Rexp = 0.012	H-atom parameters not refined
RBragg = 0.053	Weighting scheme based on measured s.u.'s
χ^2 = 6.513	(Δ/σ)max = 0.001
7201 data points	Background function: Chebyshev polynomial up to the 5th order
Excluded region(s): none	Preferred orientation correction: March–Dollase (Dollase, 1986); direction of preferred orientation [001], texture parameter r = 0.970(12)

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
N1	0.9781 (8)	0.4679 (4)	0.1534 (7)	0.053 (3)*
H1	1.0252	0.4454	0.1059	0.064*
C2	0.8381 (10)	0.4637 (5)	0.1390 (8)	0.059 (4)*
N3	0.8032 (8)	0.5117 (4)	0.2275 (7)	0.056 (3)*
H3	0.7189	0.5218	0.2328	0.067*
C4	0.9415 (10)	0.5916 (5)	0.4103 (9)	0.058 (4)*
H4	0.8670	0.6094	0.4424	0.070*
C5	1.0811 (10)	0.6130 (5)	0.4622 (9)	0.062 (4)*
C6	1.1900 (10)	0.5847 (5)	0.4070 (9)	0.057 (4)*
H6	1.2807	0.6011	0.4423	0.068*
C7	1.1737 (10)	0.5362 (5)	0.3081 (9)	0.063 (4)*
H7	1.2490	0.5190	0.2767	0.076*
C8	1.0347 (10)	0.5137 (5)	0.2559 (9)	0.057 (3)*
C9	0.9220 (10)	0.5410 (5)	0.3057 (9)	0.056 (4)*
O10	1.1213 (6)	0.6614 (3)	0.5621 (5)	0.046 (2)*
C11	1.0126 (10)	0.7106 (5)	0.5916 (8)	0.056 (3)*
H11A	0.9413	0.6832	0.6217	0.067*
H11B	0.9683	0.7393	0.5160	0.067*
C12	1.0966 (10)	0.7592 (5)	0.6990 (9)	0.060 (3)*
H12A	1.0349	0.7938	0.7257	0.090*
H12B	1.1673	0.7850	0.6670	0.090*
H12C	1.1406	0.7294	0.7718	0.090*
S13	0.7215 (3)	0.42270 (14)	0.0146 (2)	0.0510 (10)*
C14	0.5594 (10)	0.4127 (5)	0.0751 (9)	0.063 (4)*
H14A	0.5508	0.4518	0.1349	0.076*
H14B	0.4768	0.4125	0.0039	0.076*
C15	0.5808 (10)	0.3356 (5)	0.1471 (9)	0.065 (4)*
H15A	0.5826	0.2963	0.0857	0.078*
H15B	0.6678	0.3348	0.2131	0.078*
N16	0.4543 (8)	0.3275 (4)	0.2089 (7)	0.062 (3)*
H16	0.3777	0.3445	0.1505	0.074*
C17	0.4721 (10)	0.3743 (5)	0.3303 (9)	0.063 (3)*
H17A	0.5588	0.3614	0.3912	0.076*
H17B	0.4769	0.4255	0.3077	0.076*
C18	0.3493 (10)	0.3620 (5)	0.3923 (9)	0.057 (3)*
H18A	0.3618	0.3910	0.4710	0.068*
H18B	0.2634	0.3779	0.3332	0.068*
O19	0.3379 (6)	0.2867 (3)	0.4230 (5)	0.048 (2)*
C20	0.3036 (9)	0.2454 (5)	0.3042 (9)	0.056 (3)*
H20A	0.2192	0.2651	0.2477	0.067*
H20B	0.2860	0.1948	0.3229	0.067*
C21	0.4272 (10)	0.2498 (5)	0.2354 (9)	0.057 (3)*
H21A	0.5105	0.2283	0.2903	0.068*
H21B	0.4042	0.2226	0.1545	0.068*
Cl1	0.1768 (3)	0.37260 (14)	0.0310 (2)	0.0500 (9)*
Cl2	0.5313 (3)	0.56770 (14)	0.2831 (2)	0.0470 (9)*

Geometric parameters (Å, º)

N1—C2	1.346 (12)	C12—H12C	0.96
N1—C8	1.381 (11)	S13—C14	1.851 (11)
N1—H1	0.86	C14—C15	1.592 (13)
C2—N3	1.381 (12)	C14—H14A	0.97
C2—S13	1.705 (9)	C14—H14B	0.97
N3—C9	1.372 (11)	C15—N16	1.533 (14)
N3—H3	0.86	C15—H15A	0.97
C4—C5	1.407 (13)	C15—H15B	0.97
C4—C9	1.420 (13)	N16—C21	1.483 (12)
C4—H4	0.93	N16—C17	1.518 (12)
C5—O10	1.364 (11)	N16—H16	0.91
C5—C6	1.425 (15)	C17—C18	1.512 (15)
C6—C7	1.352 (13)	C17—H17A	0.97
C6—H6	0.93	C17—H17B	0.97
C7—C8	1.408 (13)	C18—O19	1.424 (11)
C7—H7	0.93	C18—H18A	0.97
C8—C9	1.417 (15)	C18—H18B	0.97
O10—C11	1.480 (12)	O19—C20	1.437 (10)
C11—C12	1.525 (12)	C20—C21	1.550 (14)
C11—H11A	0.97	C20—H20A	0.97
C11—H11B	0.97	C20—H20B	0.97
C12—H12A	0.96	C21—H21A	0.97
C12—H12B	0.96	C21—H21B	0.97
C2—N1—C8	109.8 (8)	C15—C14—H14A	111.2
C2—N1—H1	125.1	S13—C14—H14A	111.2
C8—N1—H1	125.1	C15—C14—H14B	111.2
N1—C2—N3	106.9 (7)	S13—C14—H14B	111.2
N1—C2—S13	126.7 (8)	H14A—C14—H14B	109.1
N3—C2—S13	125.1 (7)	N16—C15—C14	105.0 (7)
C9—N3—C2	110.4 (8)	N16—C15—H15A	110.8
C9—N3—H3	124.8	C14—C15—H15A	110.7
C2—N3—H3	124.8	N16—C15—H15B	110.8
C5—C4—C9	115.5 (9)	C14—C15—H15B	110.7
C5—C4—H4	122.3	H15A—C15—H15B	108.8
C9—C4—H4	122.3	C21—N16—C17	111.7 (7)
O10—C5—C4	124.4 (9)	C21—N16—C15	111.7 (7)
O10—C5—C6	116.2 (8)	C17—N16—C15	111.0 (7)
C4—C5—C6	119.4 (8)	C21—N16—H16	107.4
C7—C6—C5	126.0 (9)	C17—N16—H16	107.4
C7—C6—H6	117.0	C15—N16—H16	107.4
C5—C6—H6	117.0	C18—C17—N16	109.5 (7)
C6—C7—C8	115.3 (10)	C18—C17—H17A	109.7
C6—C7—H7	122.4	N16—C17—H17A	109.8
C8—C7—H7	122.4	C18—C17—H17B	109.8
N1—C8—C7	131.5 (9)	N16—C17—H17B	109.8
N1—C8—C9	107.3 (8)	H17A—C17—H17B	108.2
C7—C8—C9	121.1 (9)	O19—C18—C17	110.7 (8)
N3—C9—C8	105.3 (8)	O19—C18—H18A	109.5
N3—C9—C4	131.9 (9)	C17—C18—H18A	109.5
C8—C9—C4	122.7 (8)	O19—C18—H18B	109.5
C5—O10—C11	117.6 (6)	C17—C18—H18B	109.5
O10—C11—C12	102.7 (7)	H18A—C18—H18B	108.1
O10—C11—H11A	111.2	C18—O19—C20	108.9 (6)
C12—C11—H11A	111.2	O19—C20—C21	109.3 (7)
O10—C11—H11B	111.3	O19—C20—H20A	109.8
C12—C11—H11B	111.3	C21—C20—H20A	109.8
H11A—C11—H11B	109.1	O19—C20—H20B	109.9
C11—C12—H12A	109.5	C21—C20—H20B	109.8
C11—C12—H12B	109.5	H20A—C20—H20B	108.2
H12A—C12—H12B	109.5	N16—C21—C20	109.3 (8)
C11—C12—H12C	109.5	N16—C21—H21A	109.8
H12A—C12—H12C	109.4	C20—C21—H21A	109.8
H12B—C12—H12C	109.5	N16—C21—H21B	109.8
C2—S13—C14	104.7 (5)	C20—C21—H21B	109.8
C15—C14—S13	102.9 (6)	H21A—C21—H21B	108.3

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···Cl1^i	0.86	2.26	3.104 (8)	165
N3—H3···Cl2	0.86	2.19	3.032 (8)	165
N16—H16···Cl1	0.91	2.14	3.043 (8)	171
C14—H14A···Cl2	0.97	2.67	3.634 (10)	176
C17—H17B···Cl2	0.97	2.68	3.633 (10)	169
C18—H18A···Cl2^ii	0.97	2.68	3.599 (9)	160
C21—H21B···O19^iii	0.97	2.39	3.285 (11)	153

Symmetry codes: (i) x+1, y, z; (ii) −x+1, −y+1, −z+1; (iii) x, −y+1/2, z−1/2.